Angiogenesis plays an important role in embryogenesis and tumorigenesis. It is a complicated multistep process, which includes the dynamic changes of cell-cell and cell-matrix interactions, endothelial cell proliferation and migration, recruitment of the peri-vascular supporting cells, and the maturation process. Numerous molecules are involved in those processes, including growth factors and their receptors, proteases, adhesion receptors, and the ECM1 components. VEGF and angiopoietin families play special roles in angiogenesis due to the restricted expression of their receptors.
Ang-1 and Ang-2 are approximately 70 kDa proteins with considerable sequence homology that consist of a signal peptide, an N-terminal coiled-coil domain, a short linker peptide region, and a C-terminal fibrinogen homology domain (FHD). The coiled-coil region is responsible for dimerization/multimerization of angiopoietins, and the fibrinogen homology domain binds to Tie-2 receptor. Both Ang-1 and Ang-2 form dimers and oligomers.
Ang-1 and Ang-2 have antagonistic roles. Ang-1 induces tyrosine phosphorylation of Tie-2 receptor and promotes recruitment of the pericytes and smooth muscle cells, thereby playing a role in establishing and maintaining the vascular integrity. As an antagonist of Tie-2 receptor, Ang-2 competes with Ang-1 for the binding of Tie-2, Ang-2 blocks the phosphorylation of Tie-2 receptors induced by Ang-1, and Ang-2 loosens the interactions between endothelial and peri-vascular support cells and ECM.
Targeted disruption of Ang-1 and Tie-2 and overexpression of Ang-2 resulted in embryonic death with the similar vascular defects. These mice have normal primary vascular development, but the remodeling and maturation of the vasculature are defective. The transgenic mice overexpressing Ang-1 displayed increased vascularization and decreased adult vasculature leakage. Together, these results indicated that Ang-1 plays an indispensable role in the formation of blood vessels during mouse development by recruiting and maintaining peri-endothelial support cells.
Several studies have offered possible mechanisms for the pro-angiogenic effect of Ang-1. Although Ang-1 does not stimulate the proliferation of endothelial cells, it stimulates endothelial cell migration, induces the capillary-like tubule formation, and promotes survival of endothelial cells. Ang-1 inhibits apoptosis of endothelial cells via the phosphatidylinositol 3-kinase/Akt pathway.
Angiogenesis is regulated by the precise balance between pro- and anti-angiogenic factors. Ang-2 expression is often induced in the endothelia undergoing active remodeling or regression, by hypoxia, and several growth factors, including VEGF. Ang-2 destabilizes the vasculature. Thus, Ang-2 initiates angiogenesis in the presence of VEGF, which supplies endothelial cells with necessary survival and proliferation signals, or induces apoptosis of endothelial cells in the absence of the pro-angiogenic factors.